`(pentoxifylline)
`Tablets, 400 mg
`
`DESCRIPTION
`
`TRENTAL® (pentoxifylline) tablets for oral administration contain 400 mg of the active drug
`and the following inactive ingredients: FD&C Red No. 3, hypromellose USP, magnesium
`stearate NF, polyethylene glycol NF, povidone USP, talc USP, titanium dioxide USP, and
`hydroxyethyl cellulose USP in an extended-release formulation. TRENTAL is a tri-substituted
`xanthine derivative designated chemically as 1-(5-oxohexyl)-3, 7-dimethylxanthine that, unlike
`theophylline, is a hemorrheologic agent, i.e. an agent that affects blood viscosity. Pentoxifylline
`is soluble in water and ethanol, and sparingly soluble in toluene. The CAS Registry Number is
`6493-05-6.
`
`The chemical structure is:
`
`CH3
`N
`
`N
`
`O
`
`N
`
`N
`CH3
`
`O
`
`CH CCH CH CH CH
`3
`2
`2
`2
`
`2 O
`
`CLINICAL PHARMACOLOGY
`
`Mode of Action
`
`Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its
`viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the
`affected microcirculation and enhances tissue oxygenation. The precise mode of action of
`pentoxifylline and the sequence of events leading to clinical improvement are still to be defined.
`Pentoxifylline administration has been shown to produce dose-related hemorrheologic effects,
`lowering blood viscosity, and improving erythrocyte flexibility. Leukocyte properties of
`hemorrheologic importance have been modified in animal and in vitro human studies.
`Pentoxifylline has been shown to increase leukocyte deformability and to inhibit neutrophil
`adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by
`therapeutic doses of pentoxifylline in patients with peripheral arterial disease.
`
`Pharmacokinetics and Metabolism
`
`After oral administration in aqueous solution pentoxifylline is almost completely absorbed. It
`undergoes a first-pass effect and the various metabolites appear in plasma very soon after dosing.
`Peak plasma levels of the parent compound and its metabolites are reached within 1 hour. The
`major metabolites are Metabolite l (1-[5-hydroxyhexyl]-3,7-dimethylxanthine) and Metabolite V
`(1-[3-carboxypropyl]-3,7-dimethylxanthine), and plasma levels of these metabolites are 5 and 8
`times greater, respectively, than pentoxifylline.
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`BMS 2013
`MYLAN v. BMS
`IPR2018-00892
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`Following oral administration of aqueous solutions containing 100 to 400 mg of pentoxifylline,
`the pharmacokinetics of the parent compound and Metabolite l are dose-related and not
`proportional (non-linear), with half-life and area under the blood-level time curve (AUC)
`increasing with dose. The elimination kinetics of Metabolite V are not dose-dependent. The
`apparent plasma half-life of pentoxifylline varies from 0.4 to 0.8 hours and the apparent plasma
`half-lives of its metabolites vary from 1 to 1.6 hours. There is no evidence of accumulation or
`enzyme induction (Cytochrome P450) following multiple oral doses.
`
`Excretion is almost totally urinary; the main biotransformation product is Metabolite V.
`Essentially no parent drug is found in the urine. Despite large variations in plasma levels of
`parent compound and its metabolites, the urinary recovery of Metabolite V is consistent and
`shows dose proportionality. Less than 4% of the administered dose is recovered in feces. Food
`intake shortly before dosing delays absorption of an immediate-release dosage form but does not
`affect total absorption. The pharmacokinetics and metabolism of TRENTAL have not been
`studied in patients with renal and/or hepatic dysfunction. The pentoxifylline AUC was increased
`and elimination rate decreased in an older population (60-68 years, n=6) compared to younger
`individuals (22-30 years, n=6) (see PRECAUTIONS, Geriatric Use).
`
`After administration of the 400 mg extended-release TRENTAL tablet, plasma levels of the
`parent compound and its metabolites reach their maximum within 2 to 4 hours and remain
`constant over an extended period of time. Coadministration of TRENTAL tablets with meals
`resulted in an increase in mean Cmax and AUC by about 28% and 13% for pentoxifylline,
`respectively. Cmax for Metabolite 1 also increased by about 20%. The extended release of
`pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for improved
`gastrointestinal tolerance.
`
`INDICATIONS AND USAGE
`
`TRENTAL is indicated for the treatment of patients with intermittent claudication on the basis of
`chronic occlusive arterial disease of the limbs. TRENTAL can improve function and symptoms
`but is not intended to replace more definitive therapy, such as surgical bypass, or removal of
`arterial obstructions when treating peripheral vascular disease.
`
`CONTRAINDICATIONS
`
`TRENTAL should not be used in patients with recent cerebral and/or retinal hemorrhage or in
`patients who have previously exhibited intolerance to this product or methylxanthines such as
`caffeine, theophylline, and theobromine.
`
`PRECAUTIONS
`
`General
`
`At the first sign of anaphylactic/anaphylactoid reaction, TRENTAL must be discontinued.
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`Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations
`of arteriosclerotic disease. TRENTAL has been used safely for treatment of peripheral arterial
`disease in patients with concurrent coronary artery and cerebrovascular diseases, but there have
`been occasional reports of angina, hypotension, and arrhythmia. Controlled trials do not show
`that TRENTAL causes such adverse effects more often than placebo, but, as it is a
`methylxanthine derivative, it is possible some individuals will experience such responses.
`Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients
`with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration,
`cerebral and/or retinal bleeding) should have periodic examinations for bleeding including,
`hematocrit and/or hemoglobin.
`
`Drug Interactions
`
`Although a causal relationship has not been established, there have been reports of bleeding
`and/or prolonged prothrombin time in patients treated with TRENTAL with and without
`anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent
`monitoring of prothrombin times, while patients with other risk factors complicated by
`hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for
`bleeding including hematocrit and/or hemoglobin.
`
`Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased
`theophylline levels and theophylline toxicity in some individuals. Such patients should be closely
`monitored for signs of toxicity and have their theophylline dosage adjusted as necessary.
`
`TRENTAL has been used concurrently with beta blockers, digitalis, diuretics, antidiabetic
`agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have
`been observed in some patients treated with TRENTAL plus nifedipine or captopril; periodic
`systemic blood pressure monitoring is recommended for patients receiving concomitant
`antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced.
`
`Postmarketing cases of increased anticoagulant activity have been reported in patients
`concomitantly treated with pentoxifylline and vitamin K antagonists. Monitoring of
`anticoagulant activity in these patients is recommended when pentoxifylline is introduced or the
`dose is changed.
`
`Carcinogenesis, Mutagenesis and Impairment of Fertility
`
`Long-term studies of the carcinogenic potential of pentoxifylline were conducted in mice and
`rats by dietary administration of the drug at doses up to 450 mg/kg (approximately 19 times the
`maximum recommended human daily dose (MRHD) in both species when based on body
`weight; 1.5 times the MRHD in the mouse and 3.3 times the MRHD in the rat when based on
`body surface area). In mice, the drug was administered for 18 months, whereas in rats, the drug
`was administered for 18 months followed by an additional 6 months without drug exposure. In
`the rat study, there was a statistically significant increase in benign mammary fibroadenomas in
`females of the 450 mg/kg group. The relevance of this finding to human use is uncertain.
`Pentoxifylline was devoid of mutagenic activity in various strains of Salmonella (Ames test) and
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`in cultured mammalian cells (unscheduled DNA synthesis test) when tested in the presence and
`absence of metabolic activation. It was also negative in the in vivo mouse micronucleus test.
`
`Pregnancy
`
`Category C. Teratogenicity studies have been performed in rats and rabbits using oral doses up to
`576 and 264 mg/kg, respectively. On a weight basis, these doses are 24 and 11 times the
`maximum recommended human daily dose (MRHD); on a body-surface-area basis, they are 4.2
`and 3.5 times the MRHD. No evidence of fetal malformation was observed. Increased resorption
`was seen in rats of the 576 mg/kg group. There are no adequate and well controlled studies in
`pregnant women. TRENTAL (pentoxifylline) should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
`
`Nursing Mothers
`
`Pentoxifylline and its metabolites are excreted in human milk. Because of the potential for
`tumorigenicity shown for pentoxifylline in rats, a decision should be made whether to
`discontinue nursing or discontinue the drug, taking into account the importance of the drug to the
`mother.
`
`Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`
`Clinical studies of TRENTAL did not include sufficient numbers of subjects aged 65 and over to
`determine whether they respond differently from younger subjects. Other reported clinical
`experience has not identified differences in responses between the elderly and younger patients.
`In general, dose selection for an elderly patient should be cautious, usually starting at the low end
`of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
`function, and of concomitant disease or other drug therapy.
`
`The active metabolite is known to be substantially excreted by the kidney, and the risk of toxic
`reactions to this drug may be greater in patients with impaired renal function. Because elderly
`patients are more likely to have decreased renal function, care should be taken in dose selection,
`and it may be useful to monitor renal function.
`
`ADVERSE REACTIONS
`
`Clinical trials were conducted using either extended-release TRENTAL tablets for up to 60
`weeks or immediate-release TRENTAL capsules for up to 24 weeks. Dosage ranges in the tablet
`studies were 400 mg bid to tid and in the capsule studies, 200-400 mg tid. The table summarizes
`the incidence (in percent) of adverse reactions considered drug related, as well as the numbers of
`patients who received extended-release TRENTAL tablets, immediate-release TRENTAL
`capsules, or the corresponding placebos. The incidence of adverse reactions was higher in the
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`capsule studies (where dose related increases were seen in digestive and nervous system side
`effects) than in the tablet studies. Studies with the capsule include domestic experience, whereas
`studies with the extended-release tablets were conducted outside the U.S.
`
`The table indicates that in the tablet studies few patients discontinued because of adverse effects.
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`INCIDENCE (%) OF SIDE EFFECTS
`
`Extended-Release Tablets
`
`Immediate-Release Capsules
`
`Commercially Available
`
`Used only for Controlled Clinical
`Trials
`
`TRENTAL
`(321)
`3.1
`
`
`
`Placebo
`(128)
`0
`
`TRENTAL
`(177)
`9.6
`
`Placebo
`(138)
`7.2
`
`0.3
`-
`-
`
`-
`0.6
`-
`2.8
`2.2
`1.2
`
`-
`1.9
`-
`1.2
`-
`0.3
`-
`
`-
`-
`-
`
`-
`-
`-
`4.7
`0.8
`-
`
`-
`3.1
`-
`1.6
`-
`0.8
`-
`
`1.1
`1.7
`2.3
`
`4.0
`9.0
`3.4
`9.6
`28.8
`4.5
`
`1.7
`11.9
`1.1
`6.2
`2.3
`-
`2.3
`
`2.2
`0.7
`0.7
`
`1.4
`3.6
`2.9
`2.9
`8.7
`0.7
`
`0.7
`4.3
`5.8
`5.8
`2.2
`-
`1.4
`
`(Numbers of Patients at Risk)
`Discontinued for Side Effect
`CARDIOVASCULAR SYSTEM
`Angina/Chest Pain
`Arrhythmia/Palpitation
`Flushing
`DIGESTIVE SYSTEM
`Abdominal Discomfort
`Belching/Flatus/Bloating
`Diarrhea
`Dyspepsia
`Nausea
`Vomiting
`NERVOUS SYSTEM
`Agitation/Nervousness
`Dizziness
`Drowsiness
`Headache
`Insomnia
`Tremor
`Blurred Vision
`
`TRENTAL has been marketed in Europe and elsewhere since 1972. In addition to the above
`symptoms, the following have been reported spontaneously since marketing or occurred in other
`clinical trials with an incidence of less than 1%; the causal relationship was uncertain:
`Cardiovascular - dyspnea, edema, hypotension.
`Digestive - anorexia, cholecystitis, constipation, dry mouth/thirst.
`Nervous - anxiety, confusion, depression, seizures, aseptic meningitis.
`Respiratory - epistaxis, flu-like symptoms, laryngitis, nasal congestion.
`Skin and Appendages - brittle fingernails, pruritus, rash, urticaria, angioedema.
`Special Senses - blurred vision, conjunctivitis, earache, scotoma.
`Miscellaneous - bad taste, excessive salivation, leukopenia, malaise, sore throat/swollen
`neck glands, weight change.
`
`A few rare events have been reported spontaneously worldwide since marketing in 1972.
`Although they occurred under circumstances in which a causal relationship with pentoxifylline
`could not be established, they are listed to serve as information for physicians. Cardiovascular —
`angina, arrhythmia, tachycardia. Digestive — hepatitis, jaundice, cholestasis, increased liver
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`enzymes; and Hemic and Lymphatic — decreased serum fibrinogen, pancytopenia, aplastic
`anemia, leukemia, purpura, thrombocytopenia. Immune system disorders — anaphylactic
`reaction, anaphylactoid reaction, anaphylactic shock.
`
`OVERDOSAGE
`
`Overdosage with TRENTAL has been reported in pediatric patients and adults. Symptoms
`appear to be dose related. A report from a poison control center on 44 patients taking overdoses
`of enteric-coated pentoxifylline tablets noted that symptoms usually occurred 4-5 hours after
`ingestion and lasted about 12 hours. The highest amount ingested was 80 mg/kg; flushing,
`hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation occurred. All
`patients recovered. In addition to symptomatic treatment and gastric lavage, special attention
`must be given to supporting respiration, maintaining systemic blood pressure, and controlling
`convulsions. Activated charcoal has been used to absorb pentoxifylline in patients who have
`overdosed.
`
`DOSAGE AND ADMINISTRATION
`
`The usual dosage of TRENTAL in extended-release tablet form is one tablet (400 mg) three
`times a day with meals.
`
`While the effect of TRENTAL may be seen within 2 to 4 weeks, it is recommended that
`treatment be continued for at least 8 weeks. Efficacy has been demonstrated in double-blind
`clinical studies of 6 months duration.
`
`Digestive and central nervous system side effects are dose related. If patients develop these
`effects it is recommended that the dosage be lowered to one tablet twice a day (800 mg/day). If
`side effects persist at this lower dosage, the administration of TRENTAL should be discontinued.
`
`HOW SUPPLIED
`
`TRENTAL (pentoxifylline) is available for oral administration as 400-mg pink film-coated
`oblong tablets imprinted Trental; supplied in bottles of 100 (NDC 0039-0078-10).
`
`Store between 59 and 86° F (15 and 30° C).
`
`Dispense in well-closed, light-resistant containers.
`
`Rx only
`
`Rev. July 2010
`
`sanofi-aventis U.S. LLC
`Bridgewater, NJ 08807
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`©2010 sanofi-aventis U.S. LLC
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